Screening environmental pollutants that are harmful to the cardiometabolic status and understanding their key toxic pathways are crucial for effective clinical intervention. Based on exposure data of 46 chemicals in a nationally representative 13,286 people, logistic regression and mixture modeling were used to preliminarily identify environmental pollutants with significant impacts on 12 indicators for cardiometabolic disorders. A total of 15 chemicals were found to be associated with the integrated latent class, among which four chemicals (perfluorononanoic acid [PFNA], perfluorooctanoic acid [PFOA], thiocyanate, and thallium) also contributed significantly to the mixture effect. We constructed the adverse outcome pathways (AOPs) for nine significant toxicants in both models of individual chemicals and the mixture for each cardiometabolic disorder. Notably, fluoroalkyl substances affect multiple aspects of hyperlipidemia by activating PPARα. We performed molecular docking and in vitro experiments to verify and supplement the toxicological mechanism of PFNA. Through binding to PPARα, PFNA increased the levels of downstream molecules including CD36 (fatty acid transfer), ACSL1 (fatty acid activation), and CPT1a (intracellular transfer for β-oxidation) and ultimately promoted the accumulation of triglycerides and lipid droplets in HepG2 cells. These markers, together with key events for other metabolic phenotypes, may be potential targets for scientific research or clinical treatment.
Introduction Per- and polyfluoroalkyl substances (PFASs) have been implicated in promoting the progression of intestinal inflammation. However, the specific mechanisms remain unclear. Objectives This study aimed to elucidate how PFASs exacerbate inflammatory bowel disease (IBD) progression by directly influencing macrophages, investigate the underlying molecular mechanisms, and explore potential interventions. Methods Primary mouse peritoneal macrophages (PMs) and a chronic colitis model were utilized to investigate the impacts of three typical PFASs, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA), on the progression of IBD to clarify the underlying mechanisms and potential interventions. Results Our study found that PFNA induced significant proinflammatory responses, characterized by marked upregulation of IL-1β and IL-18 under environmentally relevant concentrations. Mechanistically, PFNA activated the caspase-11-dependent noncanonical NLRP3 inflammasome, thereby inducing dose-dependent upregulation of caspase-1, N-GSDMD, IL-1β, and IL-18. Both caspase-11 knockdown and Z-VAD-FMK inhibition attenuated these inflammatory effects. Molecular docking suggested that PFNA might induce NLRP3 inflammasome activation by interacting with pro-caspase-11. In vivo , PFNA also aggravated IBD progression through the same pathway. Conversely, based on our previous study, myricetin was found to alleviate PFNA-induced inflammation by inhibiting the caspase-11/NLRP3 axis. Conclusion Our study reveals a molecular axis through which PFNA exacerbates intestinal inflammation and identifies myricetin as a potential intervention for IBD associated with PFNA exposure. These findings provide insights into the mechanisms of PFNA-induced intestinal toxicity and may guide the development of strategies to mitigate PFNA-associated intestinal inflammation.
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